JAK-STAT

The Janus Kinase (Jak)- Signal Transducer and Activator of Transcription (STAT) signaling pathway converts extracellular signals into intracellular action such as cell migration, proliferation, and differentiation. Jak-STAT signaling is an evolutionarily conserved process that allows a cell to respond to a variety of growth and survival signals. There are three critical components of the Jak-STAT signaling pathway: a cytokine receptor, Jak, and STAT.

During Jak-STAT signaling, Jak will bind to a transmembrane cytokine receptor, which, upon ligand binding, will cause Jak to autophosphorylate. Jak phosphorylation encourages the recruitment of STAT molecules that are, in turn, phosphorylated by Jak. STAT molecules then form hetero- or homodimers and translocate to the nucleus to initiate transcription. There are seven different STAT molecules that interact with unique DNA sequences. Activation of Jaks associated with membrane receptors can also act as docking stations for secondary signaling molecules and adaptors that can link the Jak-STAT pathway to MAPK and other signaling pathways. Suppressors of cytokine signaling (SOCS) that compete with STAT binding sites on receptors and protein inhibitors of activated STAT (PIAS) that inhibit STAT binding to DNA negatively regulate the Jak-STAT pathway.

Jak mutations are hallmarks of many haematological malignancies. For instance, mutations in Jak3 that render it constitutively active can cause acute megakaryoblastic leukemia[1]. Similarly, STAT3, which is phosphorylated during IL-6 signaling, can be oncogenic if not properly controlled; STAT3 dysregulation, therefore, can continually promote an anti-apoptotic cellular milieu[2]. Considering the impact of dysregulated Jak-STAT signaling in a variety of diseases, including inflammatory disorders and malignancies, they are currently the focus of therapeutic intervention.